Project Summary Monoclonal gammopathy of undetermined significance (MGUS) is a benign condition and its frequency increases dramatically with age: 1% of adults over 25, 3% of those over 50, and 20% of those over 90. It is reported to progress to multiple myeloma (MM) at a rate of 2% per year. Both conditions are more prevalent in men than in women, and in blacks compared to whites. We have shown that MM is characterized by frequent chromosome translocations involving the immunoglobulin (Ig) genes and hyperdiploidy. These appear to be primary genetic events, and in all cases associated with dysregulated expression of a cyclin D gene, providing a universal basis for the development of MGUS and MM. The only known genetic factors associated with progression from MGUS to MM are activating mutations of RAS, and rearrangements of MYC, however their causative role, if any, in the MGUS-MM transition has not been proven yet given the difficulty of performing biological studies on primary MM patient cells. We propose to use the genetically engineered Vk*MYC mice to study the biologic factors underlying the development and progression of MGUS. During the last funding cycle we confirmed that aging C57BL/6, but not CBA or BALB/c mice spontaneously develop MGUS. We showed that sporadic activation of a MYC transgene in individual germinal center B-cells in C57BL/6 Vk*MYC mice universally converted this phenotype to one of progressive MM, indicating a causative role for MYC dysregulation in the progression of MGUS to MM. Using a combination of high throughput technologies, including gene expression profiling and aCGH, on primary MGUS and MM tumors arising in Vk*MYC mice we will identify the genetic changes associated with tumor progression from MGUS to intra- and extra-medullary MM. Furthermore, we will take advantage of our ability to serially transplant these MM tumors in syngeneic mice to study the biology of MM cells in vivo, focusing on two fundamental aspects:study genetic factors in tumor progression and the characterization of the MM stem cell capable of reconstituting the MM tumor. Finally, using novel transgenic mice, we will functionally study the role of activation of RAS and dysregulation of cyclin D1 in the progression of MGUS to MM. In summary, by taking advantage of our unique and highly innovative mouse model of MM, will address fundamental questions concerning the susceptibility to one of the commonest age-associated pre-malignant conditions, the nature of tumor stem cells, and the genetics of multi-step tumor progression. The results will have important implications for the prognosis, prevention and treatment of individuals with MGUS, patients with MM, and cancer patients generally.